Use of bradycardiac substances in the treatment of myocardial diseases associated with hypertrophy and novel medicament combinations

ABSTRACT

The present invention relates to the new use of bradycardiac substances such as a Ca ++  channel blocker, beta-receptor blocker or i f  channel blocker, the i f  channel blockers being preferred, optionally in combination with a cardioactive substance for inducing the regression of myocardial diseases accompanied by hypertrophy, particularly for the treatment of idiopathic hypertrophic cardiomyopathies (HCM) in humans and domestic pets.

[0001] Elevated heart rate may be treated with bradycardiac substances,particularly Ca⁺⁺ channel blockers such as diltiazem and verapamil orbeta-receptor blockers such as atenolol, bisoprolol, carvedolol,metoprolol or propanolol and i_(f) channel blockers such as zatebradine[1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-propane](see EP-B-0 065 229),3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one(see EP-B-0 224 794) and its enantiomers cilobradine[(+)-3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one]or alinidine [2-(N-allyl-2,6-dichloro-anilino)-2-imidazolidine), cf.also U.S. Pat. No. 3,708,485], while zatebradine is also known to have afavourable activity in the treatment of cardiac insufficiency (seeEP-B-0 471 388).

[0002] Moreover it is known that bradycardiac substances, particularlythe abovementioned compounds, of which the i_(f) channel blockers suchas zatebradine, cilobradine or alinidine, and in particular cilobradine,are preferred, can have a beneficial effect on the symptoms ofmyocardial diseases accompanied by hypertrophy, particularly for thetreatment of idiopathic hypertrophic cardiomyopathies (HCM) such ashypertrophy of the remainder of the myocardium after myocardialinfarction, ischaemic cardiomyopathy, hypertrophy of the myocardium invalve defects and myocarditis under toxic or iatrogenic influences.

[0003] Surprisingly it has now been found that bradycardiac substances,of which the i_(f) channel blockers such as zatebradine, cilobradine oralinidine, and in particular cilobradine, are preferred, not only have afavourable effect on the clinical symptoms of hypertrophiccardiomyopathy, but will even induce regression of these serious heartdiseases.

[0004] The present invention thus relates to the new use of bradycardiacsubstances, particularly the abovementioned compounds, of which thei_(f) channel blockers such as zatebradine, cilobradine or alinidine,and in particular cilobradine, are preferred, to induce the regressionof myocardial diseases accompanied by hypertrophy, particularly for thetreatment of idiopathic hypertrophic cardiomyopathies (HCM) in humansand domestic pets.

[0005] In order to achieve the effect according to the invention it isexpedient to use the dosage known from the literature for the treatmentof elevated heart rate for the individual bradycardiac substances. Forexample the single dose

[0006] for cilobradine is 0.1 to 0.5 mg/kg per os, preferably 0.2 to 0.4mg/kg, 1 to 3× daily,

[0007] for zatebradine it is 0.2 to 1 mg/kg 2× daily and

[0008] for alinidine it is 0.5 to 5 mg/kg 2× daily.

[0009] The new use of the bradycardiac substances according to theinvention was investigated with the i_(f) channel blocker—cilobradine byway of example, using the following method:

[0010] A cat with severe hypertrophic cardiomyopathy (heart rate about200 beats/minute), ECG with ST accentuations as a sign of myocardialischaemia, increased creatinine kinase activity in the plasma and in theultrasound image, massive compression of the ventricular wall with areduction in the ventricular volume and the ejection fraction, exhibiteda significant improvement in clinical symptoms after treatment with thei_(f) channel blocker cilobradine (0.3 mg/kg per os, 2× daily) (relieffrom pain, normal ECG, return of normal physiological activity pattern).

[0011] Follow-up investigations after one year and after about 2 years'treatment surprisingly showed a regression in myocardial hypertrophywhile the improvement in symptoms was maintained.

[0012] The hypertrophic cardiomyopathy in the cat serves as a model forthe corresponding disease in humans (Kittleson et al., Circulation 91,3172-3180 (1999)).

[0013] Treatment with the i_(f) channel blocker cilobradine thus leadsnot only to an improvement in symptoms but also to regression of thedisease.

[0014] The present invention also relates to drug combinations,containing at least one bradycardiac substance, particularly one of theabovementioned compounds, preferably an i_(f) channel blocker, and atleast one cardioactive substance such as

[0015] a cardioglycoside, e.g. methyldigoxin or digitoxin,

[0016] a vasodilator, e.g. nitroglycerine,

[0017] an ACE inhibitor, e.g. captopril or enalapril,

[0018] an angiotensin-II antagonist, e.g. losartan or telmisartan,

[0019] which are also suitable for treating myocardial diseasesaccompanied by hypertrophy, particularly for the treatment of idiopathichypertrophic cardiomyopathies (HCM), if a rise in heart rate can beprevented by combining them with a bradycardiac substance.

[0020] To achieve the effect according to the invention it is convenientto use the dosages known from the literature for the individualbradycardiac substances for the treatment of elevated heart rate and thedosages known from the literature for the cardioactive compound used.

[0021] For this purpose the bradycardiac substances, either on their ownor combined with other cardioactive compounds, are formulated with oneor more conventional inert carriers and/or diluents, e.g. with maizestarch, lactose, glucose, microcrystalline cellulose, magnesiumstearate, polyvinylpyrrolidone, citric acid, tartaric acid, water,water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol,propyleneglycol, stearyl alcohol, carboxymethylcellulose or fattysubstances such as hard fat or suitable mixtures thereof, to produceconventional Galenic preparations such as plain or coated tablets,capsules, powders, suspensions, solutions, sprays or suppositories.

[0022] Thus, for example, the combination consisting of cilobradine anda cardioactive compound conveniently contains 0.1 to 0.5 mg/kg,preferably 0.2 to 0.4 mg/kg of cilobradine per os

[0023] plus 0.01 to 1 mg of methyldigoxin, 1 to 2× daily,

[0024] 0.01 to 1 mg of digoxin, 1× daily,

[0025] 0.1 to 2 mg of nitroglycerine, 2 to 3× daily,

[0026] 10 to 100 mg of captopril, 1 to 2× daily,

[0027] 2 to 20 mg of enalapril, 1× daily,

[0028] 10 to 200 mg of losartan, 2× daily, or

[0029] 20 to 80 mg of telmisartan, 1× daily.

[0030] As the partners for the i_(f) channel blockers in the drugcombination additionally act on an independent biological system andi_(f) channel blockers inhibit reflex increases in heart rate, which mayoccur in connection with the above combination partner, these have asynergistic activity.

[0031] The Examples that follow are intended to illustrate the inventionwithout restricting it:

EXAMPLE 1

[0032] Capsules containing 1.25 mg of cilobradine Composition: 1 capsulecontains: lactose monohydrate 82.75 mg maize starch  55.3 mg

[0033] Method of Preparation

[0034] The active substance, lactose monohydrate and maize starch aremixed and packed into size 4 capsules.

EXAMPLE 2

[0035] Capsules containing 10 mg of cilobradine Composition: 1 capsulecontains: lactose monohydrate 77.6 mg maize starch 51.7 mg

[0036] Method of Preparation

[0037] The active substance, lactose monohydrate and maize starch aremixed and packed into size 4 capsules.

EXAMPLE 3

[0038] Tablets containing 7.5 mg of cilobradine Composition: 1 tabletcontains: active substance 7.5 mg maize starch 59.5 mg lactose 48.0 mgpolyvinylpyrrolidone 4.0 mg magnesium stearate 1.0 mg 120.0 mg

[0039] Method of Preparation

[0040] The active substance, maize starch, lactose andpolyvinylpyrrolidone are mixed and moistened with water. The moistmixture is forced through a sieve with a 1.5 mm mesh and dried at 45° C.The dry granules are passed through a sieve with a 1.0 mm mesh and mixedwith magnesium stearate. The finished mixture is compressed in a tabletpress with punches 7 mm in diameter provided with a dividing notch, toform tablets.

[0041] Weight of tablet: 120 mg

EXAMPLE 4

[0042] Coated tablets containing 5 mg of cilobradine 1 tablet corecontains: active substance 5.0 mg maize starch 41.5 mg lactose 30.0 mgpolyvinylpyrrolidone 3.0 mg magnesium stearate 0.5 mg 80.0 mg

[0043] Method of Preparation

[0044] The active substance, maize starch, lactose andpolyvinylpyrrolidone are mixed thoroughly and moistened with water. Themoist mass is forced through a sieve with a 1.0 mm mesh and dried at 45°C., then the granules are passed through the same sieve. After mixingwith magnesium stearate, convex tablet cores with a diameter of 6 mm arecompressed in a tablet-making machine. The tablet cores thus producedare coated in known manner with a coated consisting essentially of sugarand talc. The finished coated tablets are polished with wax.

[0045] Weight of coated tablet: 130 mg

EXAMPLE 5

[0046] Ampoules containing 5 mg of cilobradine 1 ampoule contains:active substance  5.0 mg sorbitol 50.0 mg water for injections ad  2.0mg

[0047] Method of Preparation

[0048] In a suitable mixing vessel the active substance is dissolved inwater for injections and the solution is made isotonic with sorbitol.

[0049] After filtration through a diaphragm filter, the solution istransferred into purified and sterilised ampoules under N₂ andautoclaved for 20 minutes in a stream of water vapour.

EXAMPLE 6

[0050] Suppositories containing 10 mg of cilobradine 1 suppositorycontains: active substance 0.010 g hard fat (e.g. Witepsol H 19 and W45) 1.690 g 1.700 g

[0051] Method of Preparation

[0052] The hard fat is melted. At 38° C. the ground active substance ishomogeneously dispersed in the melt. This is cooled to 35° C. and pouredinto slightly chilled suppository moulds.

EXAMPLE 7

[0053] Drops solution containing 10 mg of cilobradine 100 ml of solutioncontain: active substance 0.2 g hydroxyethylcellulose 0.15 g tartaricacid 0.1 g sorbitol solution, 70% dry matter 30.0 g glycerol 10.0 gbenzoic acid 0.15 g dist. water ad 100 ml

[0054] Method of Preparation

[0055] The distilled water is heated to 70° C. Thehydroxyethylcellulose, benzoic acid and tartaric acid are dissolvedtherein with stirring. The solution is cooled to ambient temperature andthe glycerol and the sorbitol solution are added with stirring. Atambient temperature the active substance is added and the mixture isstirred to dissolve it completely. It is then evacuated with stirring toeliminate air from the syrup.

1. Pharmaceutical compositions for the treatment of myocardial diseasesaccompanied by hypertrophy, containing a bradycardiac substance andoptionally a cardioactive compound.
 2. Pharmaceutical compositionsaccording to claim 1, characterised in that a Ca⁺⁺ channel blocker,beta-receptor blocker or i_(f) channel blocker is used as thebradycardiac substance.
 3. Pharmaceutical compositions according toclaim 1, characterised in that an i_(f) channel blocker is used as thebradycardiac substance.
 4. Pharmaceutical compositions according toclaim 3, characterised in that zatebradine, cilobradine or alinidine isused as the i_(f) channel blocker.
 5. Pharmaceutical compositionsaccording to claim 3, characterised in that cilobradine is used as thei_(f) channel blocker.
 6. Pharmaceutical compositions according toclaims 1 to 5, characterised in that they contain as a furthercardioactive compound a cardioglycoside, a vasodilator, an ACE-inhibitoror an angiotensin-II antagonist.
 7. Use of the active substances definedin claims 1 to 6 for the treatment of myocardial diseases accompanied byhypertrophy.
 8. Use of the active substances defined in claims 1 to 6for preparing a pharmaceutical composition which is suitable for thetreatment of myocardial diseases accompanied by hypertrophy.